Approximately one-third of hospital inpatients experience hyperglycemia, with up to a third of these individuals having no previous history of diabetes.12–14 Although a substantial portion of these patients likely have prediabetes or undiagnosed diabetes, acute injury and illness clearly can lead to glucose elevations in those with previously normal glucose tolerance. This stress hyperglycemia results from a complex interplay between inflammatory cytokines, catecholamines, the oxidative stress resulting from gluco- and lipotoxicity, and activation of the hypothalamic-pituitary-adrenal axis, all resulting in insulin resistance and insufficient pancreatic insulin secretion. Treatments commonly used among inpatients, such as glucocorticoids, enteral and parenteral nutrition, and vasopressors also may lead to or exacerbate glucose elevations.15 Regardless of the cause, however, hyperglycemia, particularly when severe, must be treated to reduce adverse outcomes, including dehydration, electrolyte disturbance, infectious complications, and poor wound healing.
Hyperglycemia and Adverse Hospital Outcomes
Epidemiologic studies began to establish a clear link between increasing blood glucose levels and hospital mortality in the late 1990s and early 2000s. In a 1999 publication from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, the risk of death among 620 patients with diabetes admitted for acute myocardial infarction (MI) rose by 8% with each 18 mg/dL increase in admission blood glucose (relative risk [RR] 1.08, 95% confidence interval [CI] 1.05–1.11; P < 0.001).16 A 2003 retrospective review of data from ICU patients revealed that the mortality rate approximately doubled among patients with a mean glucose value during hospitalization between 160 and 199 mg/dL and roughly tripled among patients with mean glucose between 200 and 299 mg/dL. Above 300 mg/dL, the rate of death was approximately fourfold higher.17 In a large retrospective study of more than 250,000 admissions to 173 hospitals published in 2009, the risk of death nearly doubled for patients with blood glucose 146–199 mg/dL during hospitalization (odds ratio [OR] 1.31; 95% CI 1.26–1.36), independent of severity of illness. The odds of death, adjusted for illness severity, more than doubled at 200–299 mg/dL (OR 1.82; 95% CI 1.74–1.90), and almost tripled for glucose values >300 mg/dL (OR 2.85; 95% CI 2.58–3.14).18 Other observational and controlled studies have unequivocally supported the association between hyperglycemia and inpatient mortality risk.14,19–21 In addition, patients with hyperglycemia are more likely to have prolonged hospital stays, infections, and greater degrees of disability after hospital discharge.14,21–23 Data from outside the ICU further establish the association of hyperglycemia with adverse outcomes. For example, in a study of 2,471 patients with community acquired pneumonia, blood glucose levels >200 mg/dL during hospitalization were associated with higher rates of mortality and in-hospital complications than blood glucose levels <200 mg/dL.24
Patients at greatest risk for adverse hospital outcomes may be those without a previous history of diabetes, which emphasizes the importance of treating inpatient hyperglycemia regardless of the cause. A retrospective review of medical records of more than 2,000 critically ill patients showed significant increases in mortality among patients with new hyperglycemia, that is, those without previously diagnosed diabetes. The mortality rate was about eight times higher among patients with hyperglycemia as those with normal glucose levels (P < 0.01) and about five times higher than patients with diagnosed diabetes (P < 0.01).14 In the aforementioned retrospective study of 250,000 admissions, the odds of mortality were significantly higher for patients with no previous history of diabetes than for those with diagnosed diabetes (P < 0.01). Compared with normoglycemic patients, those without diagnosed diabetes had a 35% increased risk of death if their glucose was 111–145 mg/dL (OR 1.35; 95% CI 1.30–1.41). Successively increasing glucose ranges were associated with a doubled, tripled, and quadrupled mortality risk (146–199 mg/dL: OR 2.14, 95% CI 2.04–2.24; 200–299 mg/dL: OR 2.91, 95% CI 2.71–3.11; >300 mg/dL: OR 4.04, 95% CI 3.44–4.75).18 Observational studies such as these can only be considered hypothesis generating. Indeed, because the degree of illness will be associated with the level of stress hyperglycemia, studies such as these are particularly prone to influence by unmeasured confounders. It is only through randomized clinical trials that one may know whether glucose control actually improves the risk of adverse outcomes in hospitalized patients with hyperglycemia.
Effects of Glycemic Control on Inpatient Outcomes
Both retrospective and prospective controlled studies have brought us to our current understanding of optimal glucose control for both critically ill and noncritically ill patients. In the DIGAMI study, 1-year mortality significantly decreased by 29% (P = 0.027) in patients with diabetes randomly assigned to insulin-glucose infusion for the first 24 h after acute MI compared with patients given standard therapy of the time, in which insulin was given during the first 24 h only if it was deemed clinically necessary.25 Other early controlled trials comparing tight glucose control to standard treatment approaches also demonstrated significant reductions in mortality and morbidity among both ICU and noncritical inpatient populations. In an often-cited 2001 prospective, randomized clinical trial involving 1,548 surgical ICU patients in Belgium, intensive insulin therapy to maintain glycemia between 80 and 110 mg/dL significantly reduced mortality risk by 32% (P < 0.04) compared with standard treatment of the time, in which insulin was given only when patients’ blood glucose exceeded 215 mg/dL, with the goal of maintaining blood glucose values of 180-200 mg/dL. In addition, intensive insulin therapy also significantly reduced the duration of ICU stays and ventilatory support, need for dialysis, and episodes of septicemia.1 These results were supported by a retrospective analysis of ICU patients who had undergone coronary artery bypass grafting (CABG). The investigators compared hospital records from two time periods during which different glucose control approaches had been used. During the earlier period, subcutaneous (SQ) insulin had resulted in a mean glucose value of 213 mg/dL among CABG patients, whereas a later protocol using insulin infusion resulted in a mean glucose value of 177 mg/dL. Insulin infusion reduced the risk of death by 57% (OR 0.43; P = 0.001).19
Further investigations, however, were not able to confirm the benefit of near normalization of glucose and raised concerns regarding the risk of hypoglycemia with this approach. In 2003, the same Belgian investigators published results from a second clinical trial, showing that tight glucose control did not significantly reduce mortality in the medical (as opposed to surgical) ICU, except among patients whose ICU stays exceeded 5 days.26 Subsequently, the NICE-SUGAR study highlighted the dangers of hypoglycemia that accompany tight glucose control. This international investigation compared 90-day mortality in a cohort of 6,104 patients who were admitted to medical and surgical ICUs at 42 different hospitals where they were assigned randomly to glycemic targets of 81–108 mg/dL and 144–180 mg/dL. Rates of severe hypoglycemia were ~15 times greater among intensively treated patients (OR 14.7, 95% CI 9.0–25.9; P < 0.001), and mortality was 14% higher in the same group compared with patients whose glucose was less intensively controlled (P = 0.02).9 A meta-analysis of 26 randomized controlled trials involving 13,567 ICU patients (including the NICE-SUGAR cohort) supported the NICE-SUGAR finding that the risk of hypoglycemia is too great to justify near-normal glucose values, especially in medical ICU patients. In the pooled analysis of studies reporting hypoglycemia, the relative risk of hypoglycemia was 6.0 (95% CI 4.5–8.0) for intensive insulin therapy compared with conventional glucose control. Meanwhile, the overall relative risk of death was 0.93 (95% CI 0.83–1.04).8 As a result of these findings, recommendations for target glucose levels were relaxed from the euglycemic range to the values shown in Table 1.1.
Protocols for Glucose Management
A major goal of treating hyperglycemia in the hospital is patient safety, because overtreatment and undertreatment of hyperglycemia represents major quality concerns. Well-defined, validated protocols for the management of hyperglycemia will include provisions for glucose monitoring and the treatment of hypoglycemia as well as guidance on matching insulin administration to blood glucose levels and nutrition (either meals or enteral or parenteral nutrition)
